Neonatal imprinting of tolerogenic properties in stromal cells from gut-draining lymph nodes by commensal microbiota

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Foxp3+ regulatory T cells (Tregs) play a central role for the maintenance of immune homeostasis, self-tolerance and particularly mucosal tolerance. The vast majority of Foxp3+ Tregs is generated already in the thymus, however, a subset of Foxp3+ Tregs can be converted from conventional CD4+ T cells in the periphery. This peripheral de novo generation of Foxp3+ Tregs very efficiently takes place within gut-draining lymph nodes (LNs), including mesenteric LNs (mLNs). Using LN transplantations, we could recently not only demonstrate that LN stromal cells critically contribute to the high Treg-inducing capacity of gut-draining LNs, but also that these tolerogenic properties of gut-draining LNs are stably imprinted within LN stromal cells and cannot be substantially influenced either by the local microenvironment of the skin or by inflammatory perturbations such as gastrointestinal infection or chronic colitis. Importantly, contact with commensal microbiota in the neonatal phase could be identified as the microenvironmental factor being responsible for the stable imprinting of tolerogenic properties in mLN stromal cells, further emphasizing the critical role of the neonatal period for the development of a fully functional immune system.In the present project, we aim to identify the molecular mechanisms by which intestinal microbiota stably imprint tolerogenic properties within mLN stromal cells in the neonatal period. In close cooperation with other members of the Priority Programme, we will identify bacterial species and commensal microbiota-derived molecular mediators that contribute to this process, and we will increase our knowledge of the molecular pathways being epigenetically imprinted in mLN stromal cells by commensal microbiota. We will furthermore study the impact of commensal microbiota on the formation of a Treg-specific epigenetic and transcriptional signature during peripheral de novo generation of Foxp3+ Tregs. Finally, with strong support from other members of the Priority Programme, we will investigate the long-lasting consequences of neonatal infections and subsequent changes in commensal microbiota composition on the imprinting of tolerogenic properties within mLN stromal cells. Viewed as a whole, by identifying bacterial species, molecular mediators and epigenetic mechanisms that contribute to the stable imprinting of tolerogenic properties in mLN stromal cells, this interdisciplinary project will shed further light into one of the layers of the complex and intimate connection of Foxp3+ Tregs with commensal microbiota.